Low-dose IL-2 induces CD56bright NK regulation of T cells via NKp44 and NKp46.

Low-dose interleukin (IL)-2 has shown clinical benefits in patients with autoimmune and inflammatory diseases. Both regulatory T cells (Tregs ) and natural killer (NK) cells are increased in response to low-dose IL-2 immunotherapy. The role of regulatory T cells in autoimmune diseases has been extensively studied; however, NK cells have not been as thoroughly explored. It has not been well reported whether the increase in NK cells is purely an epiphenomenon or carries actual benefits for patients with autoimmune diseases. We demonstrate that low-dose IL-2 expands the primary human CD56bright NK cells resulting in a contact-dependent cell cycle arrest of effector T cells (Teffs ) via retention of the cycle inhibitor p21. We further show that NK cells respond via IL-2R-ß, which has been shown to be significant for immunity by regulating T cell expansion. Moreover, we demonstrate that blocking NK receptors NKp44 and NKp46 but not NKp30 could abrogate the regulation of proliferation associated with low-dose IL-2. The increase in NK cells was also accompanied by an increase in Treg cells, which is dependent on the presence of CD56bright NK cells. These results not only heighten the importance of NK cells in low-dose IL-2 therapy but also identify key human NK targets, which may provide further insights into the therapeutic mechanisms of low-dose IL-2 in autoimmunity.

Early intervention services for psychosis in Ireland: are we there yet?

Early intervention in psychosis (EIP) services are now a priority for Ireland's Health Service Executive (HSE). A Model of Care for EIP services has been completed after wide consultation. It has just been launched by the Minister for Mental Health and the aim now is to roll out EIP services throughout the country. The Model of Care outlines the rational, configuration, resources, governance, and quality assurance required to operate EIP services. Two models are recommended. The first is a Hub & Spoke service model for rural and smaller urban areas. The second is a Stand-Alone service model for large urban and metropolitan areas. Introducing EIP services is going to be a challenge but there are plenty of good examples overseas. They have been shown to greatly enhance local services' ability to meet the needs of people developing psychotic disorders. They bring with them better outcomes, service satisfaction and cost savings.

Attaining the age threshold for adolescent mental health services: factors associated with transition of care in the independent sector in Ireland.

OBJECTIVES: The transition from adolescent to adult mental health services (AMHS) is associated with disengagement, poor continuity of care and patient dissatisfaction. The aim of this retrospective and descriptive study was to describe the 'care pathways' in an independent mental health service when adolescents reach age 18 and to investigate the level of engagement of those who transitioned to independent AMHS. METHODS: This is a retrospective, naturalistic and descriptive study in design. All patients discharged from the St Patrick's Adolescent Mental Health Service aged 17 years and 6 months and older, during a 3-year period between January 2014 and December 2016, were included. Electronic records were used to collect socio-demographic and clinical details and to determine engagement rates in adolescents who transferred to independent adult services. RESULTS: A total of 180 patients aged over 17 years and 6 months were discharged from the adolescent service. Of these, 45.6% were discharged to their GP, 28.9% to public mental health services and 25.6% to independent mental health services. The majority who transitioned to independent AMHS went to a Young Adult Service, which had high engagement rates at 3 and 12 months post-transition. CONCLUSIONS: In this independent mental health service, less than half of adolescents who reach the transition age are referred onto AMHS. Engagement rates were found to be high among those referred on to a specialised young adult service.

The impact of a specialized inpatient and day patient group programme on clinical outcome in older adolescents and young adults with mental illness.

Introduction Effective transition from child and adolescent mental health services (CAMHS) to adult services is one of the main challenges currently facing child psychiatry today The Young Adult 1Programme (YAP) based at St. Patrick's University Hospital Dublin, is a group based day programme especially designed to meet the needs of younger people aged 18-25 and support them through this difficult period. Aims To examine the effectiveness of participation in YAP for young adults with mental illness. To determine whether participation in particular aspects of the programme prove more beneficial and what factors might be associated with outcome. METHOD: All patients enrolled in YAP between 1 September 2011 and 31 August 2012 were included in the study. Each patient was assessed using the Health of the Nation Outcome Scales (HONOS) and Global Assessment of Functioning (GAF) rating scale before beginning the programme and after discharge in order to evaluate improvement. The frequency of attendance at individual group sessions was recorded. Patient and illness variables were also recorded, for example demographics, diagnosis. RESULTS: A total of 101 service users were in enrolled in YAP during this 12-month period. Eight service users could not be used for analysis, as they did not have a complete data set, mostly due to failure to attend for discharge HONOS/GAF ratings Using a paired sample t-test, there is a significant reduction in HONOS: Mean df=1.3, s.d.=1.09 (95% CI=1.08-1.53), p<0.001 Using a paired sample t-test, there is a significant increase in GAF: Mean df=9.25, s.d.=7.69 (95% CI=7.66-10.83), p<0.001 Improvements in HONOS and GAF scores are significantly correlated with better attendance at the programme (p<0.04, <0.00 respectively). CONCLUSION: More attendance at YAP sessions correlates with better improvement in both HONOS and GAF rating scores.

Salts of the two-coordinate homoleptic manganese(I) dialkyl anion [Mn{C(SiMe3)3}2](-) with quenched orbital magnetism.

The reduction of Mn{C(SiMe3)3}2 with KC8 in the presence of crown ethers yielded the d(6), Mn(I) salts [K2(18-crown-6)3][Mn{C(SiMe3)3}2]2 and [K(15-crown-5)2][Mn{C(SiMe3)3}2], that have near-linear manganese coordination but almost completely quenched orbital magnetism as a result of 4s-3dz(2) orbital mixing which affords a non-degenerate ground state.

Intervening early in bipolar disorder in young people: a review of the clinical staging model.

Bipolar disorder (BPD) essentially has its onset during adolescence and early adulthood. It has the capacity to be highly disruptive, dislocating individuals from their normal developmental trajectory and potentially causing significant long-term co-morbidity and chronicity. At a societal level the burden created is greater than schizophrenia. This is not helped by the very substantial delays in its diagnosis and appropriate treatment. Thus, there is a clear rationale for intervening earlier and at a younger age. However, the field of early intervention in BPD is in its infancy. One approach that conceptually provides a basis for early intervention is the Clinical Staging Model (used widely in general medicine). This article outlines how this model helps in an understanding of the emerging stages of BPD. It also summarises the interventions that might be appropriately introduced if a person progresses from an early to a late stage of the illness. Early intervention has a well-established record in psychotic disorders. If it can be realised for BPDs, then it may hold out hope of better outcomes for the next generation of young people at risk.

Inhibition of the keratinolytic subtilisin protease Sub3 from Microsporum canis by its propeptide (proSub3) and evaluation of the capacity of proSub3 to inhibit fungal adherence to feline epidermis.

Microsporum canis is a pathogenic fungus that causes a superficial cutaneous infection called dermatophytosis, mainly in cats, dogs and humans. Proteolytic enzymes have been postulated to be key factors involved in the invasion of the stratum corneum and keratinized epidermal structures. Among these proteases, the secreted subtilisin protease Sub3 was found to be required for adherence of M. canis arthroconidia to feline epidermis. This protease is synthetized as a preproenzyme consisting of a signal peptide followed by the propeptide and the protease domain. In order to assess whether the enzymatic activity of Sub3 could be responsible for the role of the protease in the adherence process, we expressed and characterized the propeptide of Sub3 and demonstrated that this propeptide is a strong inhibitor of its mature enzyme. This propeptide acts as a noncompetitive inhibitor with dissociation constants, K(I) and [Formula: see text] of 170 and 130 nM respectively. When tested for its capacity to inhibit adherence of M. canis to feline epidermis using an ex vivo adherence model made of feline epidermis, the propeptide does not prevent adherence of M. canis arthroconidia because it loses its capacity to inhibit rSub3 following a direct contact with living arthroconidia, presumably through inactivation by fungal membrane-bound proteases.

Economic impact of early intervention in people at high risk of psychosis.

BACKGROUND: Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis. METHOD: The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model. RESULTS: Over the initial 12 months from presentation, the costs of the OASIS intervention were pound1872 higher than CAU. However, after 24 months they were pound961 less than CAU. CONCLUSIONS: This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.

The pilin O-glycosylation pathway of pathogenic Neisseria is a general system that glycosylates AniA, an outer membrane nitrite reductase.

O-Glycosylation is emerging as a common posttranslational modification of surface exposed proteins in bacterial mucosal pathogens. In pathogenic Neisseria an O-glycosylation pathway modifies a single abundant protein, pilin, the subunit protein that forms pili. Here, we identify an additional outer membrane glycoprotein in pathogenic Neisseria, the nitrite reductase AniA, that is glycosylated in its C-terminal repeat region by the pilin glycosylation pathway. To our knowledge, this is the first report of a general O-glycosylation pathway in a prokaryote. We also show that AniA displays polymorphisms in residues that map to the surface of the protein. A frame-shift mutation abolishes AniA expression in 34% of Neisseria meningitidis strains surveyed, however, all Neisseria gonorrhoeae strains examined are predicted to express AniA, implying a crucial role for AniA in gonococcal biology.

Cytology and outcome of LSIL: cannot exclude HSIL compared to ASC-H.

OBJECTIVE: The cytological features associated with clinical outcome of 'LSIL cannot exclude HSIL (LSIL-H)' in comparison with 'atypical squamous cells cannot exclude HSIL (ASC-H)' are incompletely described. METHODS: LSIL-H and ASC-H Pap tests reported in a regional laboratory during a 13-month period were reviewed by two pathologists. Cytological features suspicious for HSIL were evaluated against a check list of 52 atypical features. All histology over 2 years of follow up for tests reclassified as LSIL-H and ASC-H was retrieved to determine clinical outcome. Atypical cytological features were correlated with outcome. RESULTS: The review yielded 89 LSIL-H and 86 ASC-H. The highest ranked atypical cytological feature in each group was increased nuclear cytoplasmic ratio. Clinical outcome was positive (CIN II/III or AIS) in 44 (49%) LSIL-H and 33 (38%) ASC-H. Round (P = 0.02) and naked nuclei (P = 0.009) were significant correlates of outcome amongst LSIL-H tests, but no feature correlated with outcome in the ASC-H group. CONCLUSIONS: LSIL-H is different to ASC-H because of the 11% higher frequency of a positive outcome and the cytological features associated with outcome.

A case of aripiprazole and tardive dyskinesia.

This is a case report of a 24-year-old African lady, who developed symptoms of tardive dyskinesia (TD) following 9 months of treatment with aripiprazole 15 mg. She has no family history of mental illness, not used illicit substances and has a medical diagnosis of idiopathic hypertension which is well controlled. The patient has an 18-month history of paranoid schizophrenia with three psychotic episodes, one severe enough to warrant admission. Upon discontinuation of aripiprazole and switch to quetiapine, the symptoms of TD disappeared rapidly. A PubMed search revealed one previous case report of aripiprazole and TD. The authors recommend maintaining vigilance regarding all possible side-effects irrespective of the type of antipsychotic being used.

First detection of CTX-M-28 in a Tunisian hospital from a cefotaxime-resistant Klebsiella pneumoniae strain.

A cefotaxime-resistant Klebsiella pneumoniae ML4313 was obtained from a patient from intensive care unit of Military hospital in Tunisia. This strain was resistant to beta-lactams, aminoglycosides, quinolones and phenicols, and tetracyclines. It was identified as producer of extended-spectrum beta-lactamases (ESBL) by double-disk synergy test between amoxicillin-clavulanate and cefotaxime, ceftriaxone, ceftazidime and aztreonam. The ESBL was identified as CTX-M-28 by sequencing of PCR products and by isoelectric focusing. The ESBL resistance was transferred by a 50kb plasmid. CTX-M-28 is closely related to CTX-M-15. This is the first description of this enzyme in Tunisia.

Using liquid and solid state NMR and photoluminescence to study the synthesis and solubility properties of amine capped silicon nanoparticles.

Water soluble silicon nanoparticles were prepared by the reaction of bromine terminated silicon nanoparticles with 3-(dimethylamino)propyl lithium and characterized with liquid and solid state nuclear magnetic resonance (NMR) and photoluminescence (PL) spectroscopies. The surface site dependent 29Si chemical shifts and the nuclear spin relaxation rates from an assortment of 1H-29Si heteronuclear solid state NMR experiments for the amine coated reaction product are consistent with both the 1H and 13C liquid state NMR results and routine transmission electron microscopy, ultra-violet/visible, and Fourier transform infrared measurements. PL was used to demonstrate the pH dependent solubility properties of the amine passivated silicon nanoparticles.

Immunobiological role of llama heavy-chain antibodies against a bacterial beta-lactamase.

In 1993, a fraction of antibodies (Abs) devoid of L chain was found naturally occurring in the Camelidae. They were found to lack L chains, as well as the first constant heavy-chain domain (CH(1)) and therefore they were named "heavy-chain Abs" (HCAbs). Subsequent studies focused on the functional, structural and biochemical properties of recombinant variable fragments (rVHHs) of HCAbs. It was stated that rVHHs have an augmented capacity to interact with "partially hidden" epitopes, like enzymes active sites, and have an increased stability to thermal and chemical aggression. It has been suggested that these unconventional Abs could represent an evolutionary advantage, being more efficient than conventional Abs to inhibit microbial enzymes, and thus exerting a more protective immune response against pathogens. The present work focuses on the immunobiological role of HCAbs, in their capacity to inhibit microbial enzymes. Two animal models were selected, comprising a model for common vertebrates without HCAbs (rabbits), and a model for vertebrates with both conventional and unconventional Abs (Lama glama). A recombinant bacterial beta-lactamase (CTX-M-2) was selected as the microbial enzymatic antigen. After conventional immunization schedules, neither serum titers nor serum inhibitory capacity showed significant differences when rabbits and llamas were compared. These results indicate that the a priori assumption that the adaptive immune system of camelids could be better "prepared" to respond to bacterial enzymes because of the presence of HCAbs, is not always accurate. Furthermore, when the different llama antibody isotypes and subclasses were purified, it was demonstrated that the inhibitory capacity of total serum was due exclusively to IgG(1). HCAbs not only failed to inhibit CTX-M-2, but instead they activated its enzymatic activity. Altogether, these results indicate that the hypotheses extrapolated from the rVHHs properties need to be revised; the real role of HCAbs in vivo remains unknown, as well as their evolutionary cause.

The phase-variable allele of the pilus glycosylation gene pglA is not strongly associated with strains of Neisseria gonorrhoeae isolated from patients with disseminated gonococcal infection.

The Neisseria gonorrhoeae pglA gene has two alleles, one of which is phase variable. A previous study reported that all disseminated gonococcal infection (DGI) isolates contained the phase-variable allele and proposed a causal link. In the present study of 81 strains no absolute correlation between DGI and the phase-variable pglA allele was observed.

[Genetic environment of CTX-M-2 in Klebsiella pneumoniae isolates from hospitalized patients in Uruguay]. / Entorno genético de CTX-M-2 en aislamientos de Klebsiella pneumoniae provenientes de pacientes hospitalizados en Uruguay.

We studied two CTX-M-2-producing Klebsiella pneumoniae clinical strains, K96005 and K13, isolated from hospitalized patients in Uruguay, during 1996 and 2003, respectively. The genomic surroundings of bla(CTX-M-2) were characterized by PCR-mapping and DNA sequencing. Our results show that blaCTX-M-2 is included in a complex class-1 integron (InK13), associated with an orf513 in both isolates. The genetic array of the integron, aac(6')-lb, bla(OxA,2), orfD (gene cassette region), associated with an orf513-bla(CTX-M-2), seems to be widely disseminated over the Rio de la Plata region.

Genetic characterization of pilin glycosylation and phase variation in Neisseria meningitidis.

Pili of Neisseria meningitidis are a key virulence factor, being the major adhesin of this capsulate organism and contributing to specificity for the human host. Pili are post-translationally modified by addition of either an O-linked trisaccharide, Gal (beta1-4) Gal (alpha1-3) 2,4-diacetamido-2,4,6-trideoxyhexose or an O-linked disaccharide Gal (alpha1,3) GlcNAc. The role of these structures in meningococcal pathogenesis has not been resolved. In previous studies we identified two separate genetic loci, pglA and pglBCD, involved in pilin glycosylation. Putative functions have been allocated to these genes; however, there are not enough genes to account for the complete biosynthesis of the described structures, suggesting additional genes remain to be identified. In addition, it is not known why some strains express the trisaccharide structure and some the disaccharide structure. In order to find additional genes involved in the biosynthesis of these structures, we used the recently published group A strain Z2491 and group B strain MC58 Neisseria meningitidis genomes and the unfinished Neisseria meningitidis group C strain FAM18 and Neisseria gonorrhoeae strain FA1090 genomes to identify novel genes involved in pilin glycosylation, based on homology to known oligosaccharide biosynthetic genes. We identified a new gene involved in pilin glycosylation designated pglE and examined four additional genes pglB/B2, pglF, pglG and pglH. A strain survey revealed that pglE and pglF were present in each strain examined. The pglG, pglH and pglB2 polymorphisms were not found in strain C311 musical sharp 3 but were present in a large number of clinical isolates. Insertional mutations were constructed in pglE and pglF in N. meningitidis strain C311 musical sharp 3, a strain with well-defined lipopolysaccharide (LPS) and pilin-linked glycan structures. Increased gel migration of the pilin subunit molecules of pglE and pglF mutants was observed by Western analysis, indicating truncation of the trisaccharide structure. Antisera specific for the C311 musical sharp 3 trisaccharide failed to react with pilin from these pglE and pglF mutants. GC-MS analysis of the sugar composition of the pglE mutant showed a reduction in galactose compared with C311 musical sharp 3 wild type. Analysis of amino acid sequence homologies has suggested specific roles for pglE and pglF in the biosynthesis of the trisaccharide structure. Further, we present evidence that pglE, which contains heptanucleotide repeats, is responsible for the phase variation between trisaccharide and disaccharide structures in strain C311 musical sharp 3 and other strains. We also present evidence that pglG, pglH and pglB2 are potentially phase variable.